SDZ PSC 833 (PSC) is a non-immunosuppressive cyclosporin that inhibits the multidrug transporter, P-glycoprotein. This study was designed to determine (1) the maximum tolerated dose (MTD) of the MDR modular PSC; (2) the dose of paclitaxel (T) in combination with PSC which produces an equivalent degree of myelotoxicity compared with T alone; and (3) the pharmacokinetics of T alone, PSC, and T+PSC. 28 patients with incurable cancers received T alone at 175 mg/m2/24h, 3 weeks later received PSC alone, then 10 days later received PSC+T at 52.5 mg/m2/24h. Cerebellar ataxia was the non-hematologic dose limiting toxicity for PSC and occurred in 5 patients, 3 of whom had peak PSC blood levels over 4000 ng/ml. 68 cycles of PSC+T were administered and other non-hematologic toxicity included transient hyperbilirubin-emia (23/68), increased nausea compared with T alone (6/68), vasovagal syncope (2/68), and increased fatigue and myalgias (8/68). The MTD for PSC was 5 mg/kg p.o. q6h (20 mg/kg/d). There was no increase in PSC toxicity or significant change in PSC levels with the addition of T or with multiple cycles of the combined treatment. 10 patients have received the MTD without significant toxicity. Plasma trough levels at the MTD are greater than 2000 ng/ml, which is a level that modulates MDR in vitro. With 30% of the T dose combined with PSC, 3/48 cycles had myelosuppression > full dose T alone. With a 50% dose of T combined with PSC, 9/18 cycles showed greater myelosuppression than with T alone. PSC 833 is well tolerated at a dose of 5 mg/kg q6h for 3 days. The analysis of pharmacokinetic data for T without and with PSC is ongoing. Reversal of clinical resistance to paclitaxel has been observed in 5 patients (2 breast, ovary, thymoma, pancreas) after the addition of PSC with 30% of the prior dose of T. The dose modification factor for paclitaxel with PSC appears to be 2.0 to 2.5 fold based on myelosuppression.